Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants
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Daniel Barnes
- Function : Author
- PersonId : 768315
- ORCID : 0000-0002-3781-7570
Goska Leslie
- Function : Author
- PersonId : 791342
- ORCID : 0000-0001-5756-6222
Joe Dennis
- Function : Author
- PersonId : 791341
- ORCID : 0000-0003-4591-1214
Irene Andrulis
- Function : Author
- PersonId : 806569
- ORCID : 0000-0002-4226-6435
Jacopo Azzollini
- Function : Author
- PersonId : 773228
- ORCID : 0000-0002-9364-9778
Daniel Barrowdale
- Function : Author
- PersonId : 768869
- ORCID : 0000-0003-1661-3939
Bernardo Bonanni
- Function : Author
- PersonId : 762720
- ORCID : 0000-0003-3589-2128
Trinidad Caldés
- Function : Author
- PersonId : 762555
- ORCID : 0000-0002-1038-5392
Wendy Chung
- Function : Author
- PersonId : 786377
- ORCID : 0000-0003-3438-5685
Kathleen Claes
- Function : Author
- PersonId : 791343
- ORCID : 0000-0003-0841-7372
Peter Devilee
- Function : Author
- PersonId : 763377
- ORCID : 0000-0002-8023-2009
- IdRef : 074428608
Laurence Faivre
- Function : Author
- PersonId : 757929
- ORCID : 0000-0001-9770-444X
Mark Greene
- Function : Author
- PersonId : 798122
- ORCID : 0000-0003-1852-9239
Peter Hulick
- Function : Author
- PersonId : 791345
- ORCID : 0000-0001-8397-4078
Anna Jakubowska
- Function : Author
- PersonId : 762556
- ORCID : 0000-0002-5650-0501
Paul James
- Function : Author
- PersonId : 791346
- ORCID : 0000-0002-4361-4657
Fabienne Lesueur
- Function : Author
- PersonId : 766610
- ORCID : 0000-0001-7404-4549
- IdRef : 165329939
Austin Miller
- Function : Author
- PersonId : 798123
- ORCID : 0000-0001-9739-8462
Katherine Nathanson
- Function : Author
- PersonId : 806570
- ORCID : 0000-0002-6740-0901
Heli Nevanlinna
- Function : Author
- PersonId : 762552
- ORCID : 0000-0002-0916-2976
Catherine C. Nogues
- Function : Author
- PersonId : 21280
- IdHAL : catherine-nogues
- IdRef : 030671175
Olufunmilayo Olopade
- Function : Author
- PersonId : 806571
- ORCID : 0000-0002-9936-1599
Sue Park
- Function : Author
- PersonId : 806572
- ORCID : 0000-0001-5002-9707
Michael Parsons
- Function : Author
- PersonId : 172259
- IdHAL : michael-parsons
- ORCID : 0000-0002-8091-0893
Inge Sokilde Pedersen
- Function : Author
- PersonId : 806573
- ORCID : 0000-0002-9902-8040
Paolo Peterlongo
- Function : Author
- PersonId : 762723
- ORCID : 0000-0001-6951-6855
Paolo Radice
- Function : Author
- PersonId : 763238
- ORCID : 0000-0001-6298-4111
Gad Rennert
- Function : Author
- PersonId : 766345
- ORCID : 0000-0002-8512-068X
Mark Robson
- Function : Author
- PersonId : 795764
- ORCID : 0000-0002-3109-1692
Priyanka Sharma
- Function : Author
- PersonId : 757755
- ORCID : 0000-0003-3890-3590
Dominique Stoppa-Lyonnet
- Function : Author
- PersonId : 770393
- ORCID : 0000-0002-5438-8309
Amanda Toland
- Function : Author
- PersonId : 806574
- ORCID : 0000-0002-0271-1792
Ana Vega
- Function : Author
- PersonId : 763402
- ORCID : 0000-0002-7416-5137
Jeffrey Weitzel
- Function : Author
- PersonId : 806575
- ORCID : 0000-0001-6714-092X
Siddhartha Yadav
- Function : Author
- PersonId : 806576
- ORCID : 0000-0003-4630-9903
Xin Yang
- Function : Author
- PersonId : 762750
- ORCID : 0000-0002-7506-9673
Drakoulis Yannoukakos
- Function : Author
- PersonId : 764694
- ORCID : 0000-0001-7509-3510
- IdRef : 111519055
Jacques Simard
- Function : Author
- PersonId : 757778
- ORCID : 0000-0001-6906-3390
Douglas Easton
- Function : Author
- PersonId : 782295
- ORCID : 0000-0003-2444-3247
Abstract
We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. Methods: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. Results: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10 −72). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10 −50). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10 −22) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10 −12) carriers. The associations in the prospective cohort were similar. Conclusion: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.
Origin : Publication funded by an institution